A Novel Protein Encoded by Exosomal CircATG4B Induces Oxaliplatin Resistance in Colorectal Cancer by Promoting Autophagy

Abstract

Oxaliplatin is commonly used in chemotherapeutic regimens for colorectal cancer (CRC) after surgical resection. However, acquired chemoresistance seriously affects the curative effect in CRC patients, and the mechanism is still unclear. Here, a circular RNA, circATG4B is identified, which plays an important role in oxaliplatin resistance in CRC. circATG4B expression is found to be increased in exosomes secreted by oxaliplatin‐resistant CRC cells. In addition, the results suggest that circATG4B induces oxaliplatin resistance by promoting autophagy. Further in vivo and in vitro studies indicate that the effect of circATG4B is attributed to its potential to encode a novel protein, circATG4B‐222aa. Next, circATG4B‐222aa is found to function as a decoy to competitively interact with TMED10 and prevent TMED10 from binding to ATG4B, which leads to increased autophagy followed by induction of chemoresistance. Therefore, this study reveals that exosomal circATG4B participates in the decreased chemosensitivity of CRC cells, providing a new rationale for a potential therapeutic target for oxaliplatin resistance in CRC.

CircRNAs in colorectal cancer: potential biomarkers and therapeutic targets

“…CircPLCE1 encoded a novel circPLCE1-411 protein that inhibited tumor proliferation and metastasis in CRC cells [ 54 ]. Exosomal CircATG4B encoded a novel protein and induced oxaliplatin resistance in CRC by promoting autophagy [ 55 ]. In addition, circular RNAs can be classified as IRES-dependent or IRES-independent translational machinery.…”

“…Some circRNAs such as circRS-122, circ_001680, circ_0002813, circ_101277, circ_0000236, and circ-ZEB1 are associated with chemotherapy resistance (e.g., fluorouracil (5-Fu), oxaliplatin, cisplatin, and irinotecan) in CRC [ 55 , 98 , 105 – 108 ]. For this reason, detecting the expression of these circRNAs may be useful for predicting the sensitivity of patients with CRC to chemoradiotherapy in the clinic.…”

Newly discovered mechanisms that mediate tumorigenesis and tumour progression: circRNA‐encoded proteins

“…Further studies revealed that circATG4B was highly expressed in the exosomes of oxaliplatin‐resistant colorectal cancer cells and that it was transferred to other oxaliplatin‐sensitive colorectal cancer cells via these exosomes. circATG4B encodes the protein ATG4B‐222aa, which is a decoy to prevent ATG4B from competitively binding TMED10, thereby allowing an increased amount of ATG4B to be released and accelerating autophagy, ultimately leading to increased autophagy and inducing chemoresistance in colorectal cancer cells 72 (Figure 4D).…”

“…As reported by Tang et al, HNRNPU‐603aa encoded by circHNRNPU promotes multiple myeloma progression by regulating the bone marrow microenvironment and alternative splicing events, 53 and this protein may be a potential diagnostic biomarker for multiple myeloma. Another recent study reported that ATG4B‐222aa encoded by circATG4B reduces the chemosensitivity of colorectal cancer cells by promoting autophagy 72 . Since it can act as an important biomarker, if this protein can be detected during chemotherapy, it can guide changes in the treatment plan in advance during follow‐up chemotherapy.…”

The Crosstalk and Clinical Implications of CircRNAs and Glucose Metabolism in Gastrointestinal Cancers

“…Furthermore, circRNAs are associated with drug resistance. In CRC, circNRIP1 [ 46 ] and circ_0000338 [ 47 ] confer 5-fluorouracil (5-FU) resistance and contribute to CRC progression, whereas circ_0082182 [ 48 ], hsa_circ_0005963 [ 49 ] and circATG4B [ 50 ] confer resistance to oxaliplatin.…”